The risk for osteoporotic fractures, a significant problem in the aging population, is inversely related not only to bone mass, but also to bone size. Engineering principles predict that bone size is an important determinant of bone strength. A primary determinant of bone size, and thus, bone strength, is the periosteal bone formation (PBF). There is now evidence that each of these three interrelated phenotypes are influenced by genetic factors. Our preliminary studies indicate that bone size is inherited as a polygenic trait. A powerful tool to investigate polygenic traits is the QTL mapping approach. pQCT analysis revealed that the RF/j and the NZB/BinJ strains differed by 40 percent in bone size with corresponding differences in bone strength and PBF. The goal of this application is to identify and elucidate the actions of gene(s) that determine bone size, strength and PBF. Because information about candidate genes, which may be obtained by determining the mechanism(s) leading to a given phenotype, is very helpful in identification of the specific gene, this application also intends to determine the mechanistic basis for the differences in bone size. Therefore, this application has two sets of specific aims. The first set of aims is: 1) to establish the optimum timing for expression of the bone size, strength, and PBF phenotypes in RFJ and NZB inbred strains of mice; 2) to apply QTL mapping analysis to the F2 progenies of RF/J-NZB strain pair to identify gene loci that simultaneously regulate femur bone size, bone strength, and PBF; 3) to establish genetic linkage of QTL to regions of specific chromosomes; and 4) to produce congenic strain progeny in order to fine map the location of the major common QTL genes regulating all three phenotypes. The second specific aim will determine the mechanism(s) leading to the greater bone size in the congenic strains of mice, by investigating two mechanisms which could regulate PBF: one deals with local mechanisms involving mechanical strain, and the other deals with systemic mechanisms involving systemic factors, such as serum IGF-I. If the hypothesis that genetically determined variations in PBF are a primary determinant of bone size and strength is correct, the genetic aspects of this work will reveal the chromosomal location for these genes that simultaneously control PBF, bone size and strength, and provides the framework for future work in determining the identity of these genes. The mechanistic studies with the congenic mice will yield important information on the mechanism whereby the gene understudy controls PBF, bone size and strength. Such a mechanism provides crucial information from both a biological and clinical standpoint with respect to bone fragility. Because the majority of the healing of a fracture takes place from the periosteum, it also seems likely that understanding the process of PBF could also help to understand fracture healing.